Studies recently conducted in the applicant's laboratory have permitted the molecular cloning and partial characterization encoded in the major HIV-1 subtypes A, B, C, and D from the African and North American localities. Two obstacles have been identified in the proposed use of the gp120 clones for the development of a globally efficacious subunit vaccine. One of the drawbacks is the presumed impact of strain variation on the antigenic specificity and neutralizing efficacy of gp120. The global seroprevalence of the virus subtypes A, B, C, and D has not been examined in a systematic manner. The second concern is the need to develop a vaccine formulation that would assure long-term in vivo release of the immunogenic gp120 peptides and elicit life-long sterilizing immunity. To address these important concerns, the available gp120 clones will be used to (a) determine the relative sero-prevalence of the HIV-1 subtypes A, B, C, and D; (b) optimize the technique for long-term immunization with the sero-prevalent virus subtypes A, B, C, and D; and (c) assess the type-specific or broad neutralizing efficacy of the sero-prevalent subtypes, both in vitro and in vivo in the following experiments: I.To determine and compare the global sero-prevalence of gpl20 encoded in the HIV-1 subtypes A, B, C, and D. Il.To test the possibilities that: a. Inoculation of mice with ENV.GPI2O plasmid clones derived from the seroprevalent subtypes A, B, C, and D. would achieve long-term in vivo delivery of immunogenic peptides b. Concomitant inoculation of mice with the ENV.GP120 clones from the seroprevalent subtypes A, B, C, and D elicits broadly reactive antibodies and CTL that neutralize divergent isolates at comparable efficiency. c. Inoculation with the ENV.GP120 plasmid clones elicits antibodies and CTL reactivity that neutralize the infectivity of HIV-1 for CD4 cells in the SCID mouse or primate model.